Analysis Of Liver Biopsy Specimens Research Articles

Interpretation pitfalls in immunohistochemistry of primary liver carcinoma: a retrospective analysis of liver biopsy specimens

Background: The diagnosis of primary liver carcinoma (PLC) primarily relies on routine histopathology with hematoxylin and eosin (H&E) and the supportive evidence of immunohistochemistry (IHC). Inappropriate use of immunostains without either careful histomorphological evaluation or clinical correlation may lead to misdiagnosis and inappropriate patient management. Objective: To retrospectively analyze the interpretation pitfalls in IHC as an adjunct in assessing PLCs in liver biopsy specimens at a tertiary hospital in Thailand. Materials and Methods: The archives of the Division of Pathology, Thammasat University Hospital, were searched between 2015 and 2020 using a search tool from the pathology software system and a combination of codewords, including PLC, hepatocellular carcinoma (HCC), and intrahepatic cholangiocarcinoma (iCCA). Histomorphology of PLCs in liver biopsy specimens and the corresponding immunophenotypes were retrospectively analyzed. Clinical data for each patient was retrieved from the electronic medical record. Results: One hundred fifty-three liver biopsy specimens were retrieved. There were 128 (83.7%) iCCA, 23 (15%) HCC, and 2 (1.3%) combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Six cases (3.9%) with interpretation pitfalls in IHC were analyzed. These pitfalls included incorrect subtyping of PLCs in two cases (1.3%) and PLCs misdiagnosed as metastatic cancers in four cases (2.6%). Conclusion: Interpretation pitfalls in IHC of PLCs were noted in 3.9% of the present study cohorts. Pathologists should be familiar with the histomorphology of PLCs together with their rare variants. Appropriate use of IHC as adjuncts for evaluating PLCs and correlation with clinical details were essential for rendering the correct diagnoses of PLCs. Keywords: Immunohistochemistry; Primary liver carcinoma; Interpretation

Fetuin-A Deficiency but Not Pentraxin 3, FGF-21, or Irisin, Predisposes to More Serious COVID-19 Course.

Analysis of liver biopsy specimens showed that SARS-CoV-2 might have led to liver damage. This study aimed to evaluate the role of selected hepatokines and myokines in the development and progression of COVID-19. Seventy patients with laboratory-confirmed COVID-19 and 20 healthy volunteers were enrolled in the study. Irisin, pentraxin 3, fetuin-A, and FGF-21 serum concentrations and biochemical parameters were assessed using an immunoenzymatic method with commercially available enzyme immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA) kits. Serum fetuin-A concentrations were significantly decreased in COVID-19 patients compared to healthy volunteers. The serum concentration of FGF-21 was significantly increased in obese COVID-19 patients compared to overweight ones. Moreover, the FGF-21 level was higher in COVID-19 patients diagnosed with metabolic syndrome than in patients without metabolic syndrome. PTX3 concentration was higher in COVID-19 patients with higher HOMA-IR values than those with lower HOMA-IR values. COVID-19 patients with HOMA-IR ≤ 3 and >3 had significantly lower fetuin-A levels than the control group. Irisin concentration was significantly decreased in the HOMA-IR ≤ 3 COVID-19 subgroup when comparing with the control group. Lower levels of fetuin-A observed in COVID-19 patients despite higher HOMA-IR, CRP, and ferritin levels, pneumonia, patients requiring ICU care suggests that fetuin-A deficiency predisposes to more severe COVID-19 course. Upregulated pentraxin 3 may be used as a potential predictor of COVID-19 severity.

Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis.

Genome‐wide association studies (GWASs) in European and East Asian populations have identified more than 40 disease‐susceptibility genes in primary biliary cholangitis (PBC). The aim of this study is to computationally identify disease pathways, upstream regulators, and therapeutic targets in PBC through integrated GWAS and messenger RNA (mRNA) microarray analysis. Disease pathways and upstream regulators were analyzed with ingenuity pathway analysis in data set 1 for GWASs (1,920 patients with PBC and 1,770 controls), which included 261 annotated genes derived from 6,760 single‐nucleotide polymorphisms (P < 0.00001), and data set 2 for mRNA microarray analysis of liver biopsy specimens (36 patients with PBC and 5 normal controls), which included 1,574 genes with fold change >2 versus controls (P < 0.05). Hierarchical cluster analysis and categorization of cell type–specific genes were performed for data set 2. There were 27 genes, 10 pathways, and 149 upstream regulators that overlapped between data sets 1 and 2. All 10 pathways were immune‐related. The most significant common upstream regulators associated with PBC disease susceptibility identified were interferon‐gamma (IFNG) and CD40 ligand (CD40L). Hierarchical cluster analysis of data set 2 revealed two distinct groups of patients with PBC by disease activity. The most significant upstream regulators associated with disease activity were IFNG and CD40L. Several molecules expressed in B cells, T cells, Kupffer cells, and natural killer–like cells were identified as potential therapeutic targets in PBC with reference to a recently reported list of cell type–specific gene expression in the liver. Conclusion: Our integrated analysis using GWAS and mRNA microarray data sets predicted that IFNG and CD40L are the central upstream regulators in both disease susceptibility and activity of PBC and identified potential downstream therapeutic targets.

Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease

Histologic analysis of liver biopsy specimens allows for grading and staging of nonalcoholic fatty liver disease (NAFLD). We performed a longitudinal study to investigate the long-term prognostic relevance of histologic features for patients with NAFLD. We performed a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand. Patients underwent laboratory and biopsy analyses, and were examined every 3-12 months after their diagnosis. Outcomes analyzed were overall mortality, liver transplantation, and liver-related events. Cumulative outcomes were compared by log-rank analysis. Cox proportional-hazards regression was used to estimate adjusted hazard ratios (HRs). Time at risk was determined from the date of liver biopsy to the date of outcome or last follow-up examination. Over a median follow-up period of 12.6 years (range, 0.3-35.1 y), 193 of the patients (33.2%) died or underwent liver transplantation. Features of liver biopsies significantly associated with death or liver transplantation included fibrosis stage 1 (HR, 1.88; 95% confidence interval [CI], 1.28-2.77), stage 2 (HR, 2.89; 95% CI, 1.93-4.33), stage 3 (HR, 3.76; 95% CI, 2.40-5.89), and stage 4 (HR, 10.9; 95% CI, 6.06-19.62) compared with stage 0, as well as age (HR, 1.07; 95% CI, 1.05-1.08), diabetes (HR, 1.61; 95% CI, 1.13-2.30), current smoking (HR, 2.62; 95% CI, 1.67-4.10), and statin use (HR, 0.32; 95% CI, 0.14-0.70). Twenty-six patients (4.2%) developed liver-related events; fibrosis stage 3 (HR, 14.2; 95% CI, 3.38-59.68) and stage 4 (HR, 51.5; 95% CI, 9.87-269.2) compared with stage 0, were associated significantly with the events. Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis. In a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events.

ENCODE Tiling Array Analysis Identifies Differentially Expressed Annotated and Novel 5′ Capped RNAs in Hepatitis C Infected Liver

Microarray studies of chronic hepatitis C infection have provided valuable information regarding the host response to viral infection. However, recent studies of the human transcriptome indicate pervasive transcription in previously unannotated regions of the genome and that many RNA transcripts have short or lack 3′ poly(A) ends. We hypothesized that using ENCODE tiling arrays (1% of the genome) in combination with affinity purifying Pol II RNAs by their unique 5′ m7GpppN cap would identify previously undescribed annotated and unannotated genes that are differentially expressed in liver during hepatitis C virus (HCV) infection. Both 5′-capped and poly(A)+ populations of RNA were analyzed using ENCODE tiling arrays. Sixty-four annotated genes were significantly increased in HCV cirrhotic as compared to control liver; twenty-seven (42%) of these genes were identified only by analyzing 5′ capped RNA. Thirty-one annotated genes were significantly decreased; sixteen (50%) of these were identified only by analyzing 5′ capped RNA. Bioinformatic analysis showed that capped RNA produced more consistent results, provided a more extensive expression profile of intronic regions and identified upregulated Pol II transcriptionally active regions in unannotated areas of the genome in HCV cirrhotic liver. Two of these regions were verified by PCR and RACE analysis. qPCR analysis of liver biopsy specimens demonstrated that these unannotated transcripts, as well as IRF1, TRIM22 and MET, were also upregulated in hepatitis C with mild inflammation and no fibrosis. The analysis of 5′ capped RNA in combination with ENCODE tiling arrays provides additional gene expression information and identifies novel upregulated Pol II transcripts not previously described in HCV infected liver. This approach, particularly when combined with new RNA sequencing technologies, should also be useful in further defining Pol II transcripts differentially regulated in specific disease states and in studying RNAs regulated by changes in pre-mRNA splicing or 3′ polyadenylation status.

Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites

A significant body of evidence now forces us to rethink the causes of NASH. Once thought to be a disease caused by triglyceride accumulation in hepatocytes with subsequent oxidant stress and lipid peroxidation causing inflammation and fibrosis, new data from animal studies and a limited number of human studies now provide convincing evidence that triglyceride accumulation does not cause insulin resistance or cellular injury in the liver. The lipotoxic liver injury hypothesis for the pathogenesis of NASH suggests that we need to focus our therapeutic efforts on reducing the burden of fatty acids going to the liver or being synthesized in the liver. This can be accomplished by improving insulin sensitivity at the level of adipose tissue to prevent inappropriate peripheral lipolysis and by preventing unnecessary de novo lipogenesis in the liver. Excess carbohydrates are the major substrates for de novo lipogenesis, and thus, reducing carbohydrate consumption through dietary changes and increasing muscle glucose uptake through exercise remain important cornerstones of treatment and prevention of lipotoxic liver injury, a disease hitherto called NASH.

Quantitative Assessment of Hepatic Fat of Intact Liver Tissues with Coherent Anti-Stokes Raman Scattering Microscopy

A fatty liver might progress from being a benign fatty liver, to steatohepatitis, cirrhosis, or even hepatocellular carcinoma. The great prevalence and severe outcome have warranted much investigation of the pathology and the development of effective therapies, which involve animal studies requiring critical evaluation of the hepatic fatty change. Histological examination and wet chemical analysis of liver biopsy specimens are generally employed for this purpose despite numerous procedures being involved. Using coherent anti-Stokes Raman scattering (CARS) microscopy, we have demonstrated the specific imaging of fat droplets in intact liver tissues and extracted the hepatic fat content through image analysis while eliminating laborious procedures required by traditional histopathological examination. The content of hepatic fat measured with CARS imaging was correlated strongly with that determined by biochemical analysis (R(2) = 0.89) over a pathologically significant range of the hepatic fat (from 2% to 20% of the total mass of tissue). Our work validates the quantitative assessment of fat in intact tissue through the use of CARS microscopy. When combined with the increasingly diverse animal models of diseases related to metabolic disorders of lipids, our approach is extensible to enable acquiring important insight into the genetic, environmental, and dietary factors affecting the uptake and accumulation of fat within tissues.

Magnetic Resonance Elastography for the Noninvasive Staging of Liver Fibrosis

The purpose of our study was to prospectively compare the success rate and diagnostic accuracy of magnetic resonance elastography, ultrasound elastography, and aspartate aminotransferase to platelets ratio index (APRI) measurements for the noninvasive staging of fibrosis in patients with chronic liver disease. We performed a prospective blind comparison of magnetic resonance elastography, ultrasound elastography, and APRI in a consecutive series of patients who underwent liver biopsy for chronic liver disease in a university-based hospital. Histopathologic staging of liver fibrosis according to the METAVIR scoring system served as the reference. A total of 141 patients were assessed. The technical success rate of magnetic resonance elastography was higher than that of ultrasound elastography (133/141 [94%] vs 118/141 [84%]; P = .016). Magnetic and ultrasound elastography, APRI measurements, and histopathologic analysis of liver biopsy specimens were technically successful in 96 patients. The areas under the receiver operating characteristic curves of magnetic resonance elasticity (0.994 for F >or= 2; 0.985 for F >or= 3; 0.998 for F = 4) were larger (P < .05) than those of ultrasound elasticity, APRI, and the combination of ultrasound elasticity and APRI (0.837, 0.709, and 0.849 for F >or= 2; 0.906, 0.816, and 0.936 for F >or= 3; 0.930, 0.820, and 0.944 for F = 4, respectively). Magnetic resonance elastography has a higher technical success rate than ultrasound elastography and a better diagnostic accuracy than ultrasound elastography and APRI for staging liver fibrosis.

Fluctuation of lipoprotein metabolism linked with bile acid-activated liver nuclear receptors in Alagille syndrome

Alagille syndrome (AGS) is a rare hereditary disorder exhibiting fluctuating cholestasis and dyslipidemia. Farnesoid X receptor (FXR) and liver X receptor (LXR) are hepatic nuclear receptors that regulate bile acid and lipoprotein metabolism. To investigate whether cholestasis is related to dyslipidemia and hepatic nuclear receptor expression in AGS patients, we determined the blood levels of total bile acid (TBA) and lipoprotein parameters, and examined hepatic nuclear receptor expression in three AGS children and their three incomplete AGS parents repeatedly over several years. In the AGS children, TBA level showed significant positive correlations with low-density lipoprotein-cholesterol, apolipoprotein E (apoE)-rich high-density lipoprotein-cholesterol (HDL-C), apoA-I, apoE, and cholesteryl ester transfer protein (CETP) concentrations, but negative correlation with apoE-poor HDL-C concentration. Western blot analysis of liver biopsy specimens revealed that FXR and LXR expression increased in parallel with TBA level. CETP- and ATP-binding cassette transporter A1 expression also increased with TBA level, while scavenger receptor class B type-I expression showed the opposite response. However, apoA-I expression was similar to the control level at any TBA level. In the incomplete AGS parents, TBA and lipoprotein parameters showed little fluctuation. In summary, cholestasis is closely related to dyslipidemia and hepatic nuclear receptor expression in AGS patients.

Subacute Nonsuppurative Cholangitis (Cholangitis Lenta) in Pediatric Liver Transplant Patients

Subacute nonsuppurative cholangitis (cholangitis lenta) is an uncommon yet important histological finding in liver biopsies from pediatric liver transplant recipients. The histopathological features include proliferation of bile ductules at the edges of portal tracts, inspissated bile within dilated bile ductules, absence of acute inflammation within ducts or ductules, and normal structure of interlobular bile ducts. To describe the histopathology and clinical outcomes of pediatric liver transplant recipients with subacute nonsuppurative cholangitis. This is a retrospective analysis involving review of medical records and analysis of liver-biopsy specimens by a pathologist blinded to clinical diagnosis. We identified 9 pediatric patients meeting the criteria for nonsuppurative cholangitis. These patients were compared with a control group of patients with biliary obstruction. Liver histopathology clearly distinguishes subacute nonsuppurative cholangitis from biliary obstruction and other causes of posttransplant cholestasis. Clinical biochemistry cannot reliably distinguish between the 2, although statistically significant differences existed in levels of serum total and direct bilirubin, alanine aminotransferase, and alkaline phosphatase. The rate of proven bacterial or fungal infection in the study group was 100% in contrast to a rate of 54.5% in the control group (P < .05). Graft and patient survival were similarly poor. : Finding subacute nonsuppurative cholangitis suggests the presence of severe local or systemic infection in liver-transplant recipients, and its recognition is important for clinical management.

Serum markers detect the presence of liver fibrosis: A cohort study

Histologic examination of a liver biopsy specimen is regarded as the reference standard for detecting liver fibrosis. Biopsy can be painful and hazardous, and assessment is subjective and prone to sampling error. We developed a panel of sensitive automated immunoassays to detect matrix constituents and mediators of matrix remodeling in serum to evaluate their performance in the detection of liver fibrosis. In an international multicenter cohort study, serum levels of 9 surrogate markers of liver fibrosis were compared with fibrosis stage in liver biopsy specimens obtained from 1021 subjects with chronic liver disease. Discriminant analysis of a test set of samples was used to identify an algorithm combining age, hyaluronic acid, amino-terminal propeptide of type III collagen, and tissue inhibitor of matrix metalloproteinase 1 that was subsequently evaluated using a validation set of biopsy specimens and serum samples. The algorithm detected fibrosis (sensitivity, 90%) and accurately detected the absence of fibrosis (negative predictive value for significant fibrosis, 92%; area under the curve of a receiver operating characteristic plot, .804; standard error, .02; P < .0001; 95% confidence interval, .758-.851). Performance was excellent for alcoholic liver disease and nonalcoholic fatty liver disease. The algorithm performed equally well in comparison with each of the pathologists. In contrast, pathologists' agreement over histologic scores ranged from very good to moderate (kappa = .97-.46). Assessment of liver fibrosis with multiple serum markers used in combination is sensitive, specific, and reproducible, suggesting they may be used in conjunction with liver biopsy to assess a range of chronic liver diseases.

A review of cholesterol crystals embolism

Histologic analysis of liver biopsy specimens allows for grading and staging of nonalcoholic fatty liver disease (NAFLD). We performed a longitudinal study to investigate the long-term prognostic relevance of histologic features for patients with NAFLD.We performed a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand. Patients underwent laboratory and biopsy analyses, and were examined every 3–12 months after their diagnosis. Outcomes analyzed were overall mortality, liver transplantation, and liver-related events. Cumulative outcomes were compared by log-rank analysis. Cox proportional-hazards regression was used to estimate adjusted hazard ratios (HRs). Time at risk was determined from the date of liver biopsy to the date of outcome or last follow-up examination.Over a median follow-up period of 12.6 years (range, 0.3–35.1 y), 193 of the patients (33.2%) died or underwent liver transplantation. Features of liver biopsies significantly associated with death or liver transplantation included fibrosis stage 1 (HR, 1.88; 95% confidence interval [CI], 1.28–2.77), stage 2 (HR, 2.89; 95% CI, 1.93–4.33), stage 3 (HR, 3.76; 95% CI, 2.40–5.89), and stage 4 (HR, 10.9; 95% CI, 6.06–19.62) compared with stage 0, as well as age (HR, 1.07; 95% CI, 1.05–1.08), diabetes (HR, 1.61; 95% CI, 1.13–2.30), current smoking (HR, 2.62; 95% CI, 1.67–4.10), and statin use (HR, 0.32; 95% CI, 0.14–0.70). Twenty-six patients (4.2%) developed liver-related events; fibrosis stage 3 (HR, 14.2; 95% CI, 3.38–59.68) and stage 4 (HR, 51.5; 95% CI, 9.87–269.2) compared with stage 0, were associated significantly with the events. Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis.In a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events.

Is replication of hepatitis C virus a marker of activity of infectious process? (Findings of polymerase chain reaction and morphological analysis of liver biopsy specimens).

Comparative study of replication markers of hepatitis C virus in various biological substrates and evaluation of activity of chronic HCV infection in liver biopsy specimens showed that replication of hepatitis C virus and the number of HCV-infected hepatocytes did not promote liver damage in chronic hepatitis C. These findings indicate that the expression of antiviral reactions by liver parenchyma cells plays the key role in the morphogenesis of HCV infection.

Niemann-Pick Disease Type C in Neonatal Cholestasis at a North American Center

To determine the frequency of Niemann-Pick disease type C (NPC) among children being evaluated for neonatal cholestasis during a 2-year period. Medical records were reviewed from all infants with cholestasis and all patients with NPC evaluated at our center from January 1997 through December 1998. Forty neonates with cholestasis were evaluated, including three patients diagnosed with NPC (age at diagnosis, 5-21 months) who were originally labeled as having idiopathic neonatal cholestasis (INH). Two adolescents (ages 14 and 16 years) were also diagnosed with NPC during this period, one who originally had neonatal hepatitis and cirrhosis, and the other who had hepatosplenomegaly throughout childhood. Three of the patients with NPC were Hispanic. At time of NPC diagnosis, infants had mildly delayed motor development and persistent splenomegaly with or without hepatomegaly, and the adolescents had ataxia, dysarthria, hepatosplenomegaly, and paresis of vertical gaze. The diagnosis of NPC was established by demonstrating defective cellular cholesterol esterification in cultured skin fibroblasts in three patients and a specific genetic mutation in three patients. Niemann-Pick disease type C was found in 27% of infants initially diagnosed with INH and 8% of all infants evaluated for cholestasis. Niemann-Pick disease type C should be considered in all infants with cholestasis, particularly those with splenomegaly or who are of Hispanic descent. Electron microscopy and lipid analysis of liver biopsy specimens obtained during the evaluation of neonatal cholestasis may suggest this diagnosis.

Niemann‐Pick Disease Type C in Neonatal Cholestasis at a North American Center

ABSTRACTObjectiveTo determine the frequency of Niemann‐Pick disease type C (NPC) among children being evaluated for neonatal cholestasis during a 2‐year period.MethodsMedical records were reviewed from all infants with cholestasis and all patients with NPC evaluated at our center from January 1997 through December 1998.ResultsForty neonates with cholestasis were evaluated, including three patients diagnosed with NPC (age at diagnosis, 5–21 months) who were originally labeled as having idiopathic neonatal cholestasis (INH). Two adolescents (ages 14 and 16 years) were also diagnosed with NPC during this period, one who originally had neonatal hepatitis and cirrhosis, and the other who had hepatosplenomegaly throughout childhood. Three of the patients with NPC were Hispanic. At time of NPC diagnosis, infants had mildly delayed motor development and persistent splenomegaly with or without hepatomegaly, and the adolescents had ataxia, dysarthria, hepatosplenomegaly, and paresis of vertical gaze. The diagnosis of NPC was established by demonstrating defective cellular cholesterol esterification in cultured skin fibroblasts in three patients and a specific genetic mutation in three patients. Niemann‐Pick disease type C was found in 27% of infants initially diagnosed with INH and 8% of all infants evaluated for cholestasis.ConclusionNiemann‐Pick disease type C should be considered in all infants with cholestasis, particularly those with splenomegaly or who are of Hispanic descent. Electron microscopy and lipid analysis of liver biopsy specimens obtained during the evaluation of neonatal cholestasis may suggest this diagnosis.

Ultrastructural analysis of liver biopsy specimens in diabetes mellitus associated with chronic opisthorchiasis.

Degenerative and compensatory adaptive changes in hepatocytes and other cell populations were detected in liver biopsy specimens from patients with diabetes mellitus concomitant with chronic opisthorchis invasion. The degenerative changes included alteration of hepatocyte nuclei, infiltration of the nucleoplasm with glycogen, and formation of cricoid nuclei. The cholestatic syndrome manifested in increased intracellular cholestasis. Perihepatocellular fibrosis characteristic of combined disease leads to "autonomization" of hepatocytes, "activation" of all poles of the plasmalemma, and formation of numerous microvilli not only at the biliary and sinusoidal poles, but also on lateral surfaces. These changes are directed at improvement of hepatocyte functional activity and intensification of metabolic processes.

Nonalcoholic steatohepatitis.

To determine the clinical relevance of nonalcoholic steatohepatitis (NASH) and to review the available literature on the epidemiology, clinical features, histology, pathogenesis, clinical course, and management of this condition. Pertinent articles in English identified through a MEDLINE search (1966 to the present) and the bibliographies of relevant articles. All studies, including case reports, evaluating the salient features and clinical profile of NASH. Data were selected from all articles that fit the study selection criteria. Nonalcoholic steatohepatitis is a distinct clinical entity characterized by elevated plasma liver enzyme levels and liver biopsy findings that are identical to those seen in alcoholic hepatitis; patients with NASH, however, do not consume alcohol in quantities known to cause liver injury. Patients with NASH are typically obese, middle-aged women with asymptomatic hepatomegaly who are diabetic or hyperlipidemic and present with an unrelated medical problem. Analysis of liver biopsy specimens is the cornerstone of diagnosis; hepatic morphologic findings range from mild fatty degeneration and inflammation to cell degeneration, fibrosis, and cirrhosis with or without the presence of Mallory hyaline bodies. Elevated levels of free fatty acids in the liver are thought to be responsible for the development of steatohepatitis. Although NASH is most often a benign disease with an indolent course, patients with this condition occasionally develop cirrhosis, portal hypertension, and hepatic failure. In some cases, NASH may be reversed with weight reduction. Nonalcoholic steatohepatitis is an important differential diagnosis for asymptomatic patients with chronically elevated plasma liver enzyme levels, especially if obesity, diabetes, or hyperlipidemia are present. Analysis of liver biopsy specimens is necessary for diagnosis and must be done in all patients with unexplained abnormal liver function and negative results on a noninvasive workup. Prognosis is good in most patients. The precise role of weight reduction and ursodeoxycholic acid therapy in the favorable alteration of the natural history of this disorder needs to be addressed in large, well-controlled studies.

Inhibition of experimentally induced cirrhosis in rats by hypothyroidism

The coexistence of hyperkinetic circulation, hypermetabolism, and hyperactivity of the sympathetic nervous system is encountered in both cirrhosis and hyperthyroidism. Several drugs, such as propylthiouracil and propranolol, that are beneficial for treating some patients with chronic liver diseases are also prescribed for the treatment of thyrotoxicosis. We investigated the effects of experimentally induced hypo- and hyperthyroidism on the development of cirrhosis induced in rats by thioacetamide (TAA). We specifically examined whether hypothyroidism could prevent and hyperthyroidism could aggravate liver damage. Hypothyroidism induced by methimazole (MMI, 0.04%), propylthiouracil (PTU 0.05%), and by thyroidectomy was confirmed by a significant elevation of thyroid-stimulating hormone (TSH) levels. Hyperthyroidism (decreased TSH levels) was induced by eltroxin (ELT: 50 micrograms/kg). Thirteen groups of 10 rats each were studied: euthyroid controls (3 groups: water, TAA 1.5 months, and TAA 3 months), hypothyroid (6 groups: MMI, PTU, surgical, MMI-TAA, PTU-TAA, surgical-TAA), and hyperthyroid (4 groups:ELT 1.5 months and 3 months, and ELT-TAA for 1.5 months and 3 months). Hepatic fibrosis (scored from 0 to 3) was significantly reduced (P < .0001) in hypothyroid rats as compared with euthyroid controls, and was aggravated in TAA-treated hyperthyroid rats (P < .0001). Quantitative microscopic analysis of liver biopsy specimens from all groups confirmed the semiquantitative histopathological scores (P < .001). Direct intrasplenic pressure measurement revealed a significant portal pressure elevation in the TAA and the ELT-treated rats (from 4.7 +/- 0.1 in the euthyroid group to 8.1 +/- 2.3 and 10.2 +/- 2.1 and 12.5 +/- 1.6 in the TAA, ELT and ELT- TAA groups, respectively). However, in the hypothyroid-TAA groups, the portal pressure was found to be within the euthyroid normal range (4.6 +/- 1.2 and 5.8 +/- 0.6 in the PTU-TAA and surgical-TAA, respectively). After 12 weeks, the mean spleen weight of rats receiving only TAA was significantly higher than the TAA-treated hypothyroid rats (P < .0001), indicating that the hypothyroid TAA-treated rats were less portal hypertensive. These results suggest that induced hypothyroidism can inhibit, whereas hyperthyroidism can aggravate, the development of cirrhosis in a rat model. (Hepatology 1996 Aug;24(2):419-23)

Inhibition of experimentally induced cirrhosis in rats by hypothyroidism

The coexistence of hyperkinetic circulation, hypermetabolism, and hyperactivity of the sympathetic nervous system is encountered in both cirrhosis and hyperthyroidism. Several drugs, such as propylthiouracil and propranolol, that are beneficial for treating some patients with chronic liver diseases are also prescribed for the treatment of thyrotoxicosis. We investigated the effects of experimentally induced hypo- and hyperthyroidism on the development of cirrhosis induced in rats by thioacetamide (TAA). We specifically examined whether hypothyroidism could prevent and hyperthyroidism could aggravate liver damage. Hypothyroidism induced by methimazole (MMI, 0.04%), propylthiouracil (PTU 0.05%), and by thyroidectomy was confirmed by a significant elevation of thyroid-stimulating hormone (TSH) levels. Hyperthyroidism (decreased TSH levels) was induced by eltroxin (ELT: 50 micrograms/kg). Thirteen groups of 10 rats each were studied: euthyroid controls (3 groups: water, TAA 1.5 months, and TAA 3 months), hypothyroid (6 groups: MMI, PTU, surgical, MMI-TAA, PTU-TAA, surgical-TAA), and hyperthyroid (4 groups:ELT 1.5 months and 3 months, and ELT-TAA for 1.5 months and 3 months). Hepatic fibrosis (scored from 0 to 3) was significantly reduced (P < .0001) in hypothyroid rats as compared with euthyroid controls, and was aggravated in TAA-treated hyperthyroid rats (P < .0001). Quantitative microscopic analysis of liver biopsy specimens from all groups confirmed the semiquantitative histopathological scores (P < .001). Direct intrasplenic pressure measurement revealed a significant portal pressure elevation in the TAA and the ELT-treated rats (from 4.7 ± 0.1 in the euthyroid group to 8.1 ± 2.3 and 10.2 ± 2.1 and 12.5 ± 1.6 in the TAA, ELT and ELT- TAA groups, respectively). However, in the hypothyroid-TAA groups, the portal pressure was found to be within the euthyroid normal range (4.6 ± 1.2 and 5.8 ± 0.6 in the PTU-TAA and surgical-TAA, respectively). After 12 weeks, the mean spleen weight of rats receiving only TAA was significantly higher than the TAA-treated hypothyroid rats (P < .0001), indicating that the hypothyroid TAA-treated rats were less portal hypertensive. These results suggest that induced hypothyroidism can inhibit, whereas hyperthyroidism can aggravate, the development of cirrhosis in a rat model.

Ultrastructural analysis of liver biopsy specimens in chronic hepatitis and hepatopathy

Three types of morphogenesis of a chronic general pathological process in the liver are distinguished: active hepatitis, hepatitis attended by a pronounced and early tendency toward sclerosis, and hepatopathy, a morphological phenotype of parenchymal dystrophy in the absence of a stromal inflammatory component, which is defined as a syndrome of regenerative-plastic insufficiency.